Browsing by Author "Li, Xuefei"

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    Computational Modeling of the Crosstalk Between Macrophage Polarization and Tumor Cell Plasticity in the Tumor Microenvironment
    (Frontiers, 2019) Li, Xuefei; Jolly, Mohit Kumar; George, Jason T.; Pienta, Kenneth J.; Levine, Herbert; Bioengineering; Physics and Astronomy
    Tumor microenvironments contain multiple cell types interacting among one another via different signaling pathways. Furthermore, both cancer cells and different immune cells can display phenotypic plasticity in response to these communicating signals, thereby leading to complex spatiotemporal patterns that can impact therapeutic response. Here, we investigate the crosstalk between cancer cells and macrophages in a tumor microenvironment through in silico (computational) co-culture models. In particular, we investigate how macrophages of different polarization (M1 vs. M2) can interact with epithelial-mesenchymal plasticity of cancer cells, and conversely, how cancer cells exhibiting different phenotypes (epithelial vs. mesenchymal) can influence the polarization of macrophages. Based on interactions documented in the literature, an interaction network of cancer cells and macrophages is constructed. The steady states of the network are then analyzed. Various interactions were removed or added into the constructed-network to test the functions of those interactions. Also, parameters in the mathematical models were varied to explore their effects on the steady states of the network. In general, the interactions between cancer cells and macrophages can give rise to multiple stable steady-states for a given set of parameters and each steady state is stable against perturbations. Importantly, we show that the system can often reach one type of stable steady states where cancer cells go extinct. Our results may help inform efficient therapeutic strategies.
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    Spatial distribution of B cells and lymphocyte clusters as a predictor of triple-negative breast cancer outcome
    (Springer Nature, 2021) Wortman, Juliana C.; He, Ting-Fang; Solomon, Shawn; Zhang, Robert Z.; Rosario, Anthony; Wang, Roger; Tu, Travis Y.; Schmolze, Daniel; Yuan, Yuan; Yost, Susan E.; Li, Xuefei; Levine, Herbert; Atwal, Gurinder; Lee, Peter P.; Yu, Clare C.; Bioengineering; Center for Theoretical Biological Physics
    While tumor infiltration by CD8+ T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method ‘occupancy’) to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.